Cardiovascular disease is the leading cause of death in the elderly. Studies have shown that senescent hearts are inherently more susceptible to ischemic injury. But the mechanisms of this increased susceptibility are still poorly understood. During an ischemic event, the heart must rely largetly on glucose utilization for energy supply. Alterations in glucose transporters, glucose extraction, as well as glycolytic flux have been observed in senescent hearts,suggesting that glucose utilization changes in aged myocardium. But the existing data are not consistent and are even directionally conflicting among different reports, offering no unifying picture on how glucose utilization is altered in aging hearts. Importantly, two essential questions remain unanswered: First, what are the mechanisms which contribute to the altered glucose utilization in senescent hearts? Second, what is the impact of this alteration on the susceptibility of senescent hearts toischemic damage? Combining the tools I have obtained in physiology, biochemistry and biophysics withthe new tools in molecular biology and histochemistry I propose to learn during this award period, I will be in an UNIQUE position to study glucose utilization in senescent hearts from molecular events totheir functional consequences. The GOAL of this research proposal is to define the regulation of glucose utilization under normal perfusion and during ischemia and to define its role in increased susceptibility to ischemic injury in senescent hearts. Using a widely employed animal model of aging, Fischer 344 rats, I propsoe totest two fundamental hypotheses: 1) that altered glucose utilization occurs at levels of both glucose entry and glycolysis; 2) that these alterations contribute tothe enhanced susceptibility to ischemic injury in senescent hearts. The specific aims for this proposal are: Aim 1: To test the hypothesis that there is an increase in GLUT1-mediated glucose entry and a decrease in GLUT4-mediated glucose entry in senescent hearts. Aims 2: To test the hypothesis that glucose utilization is increased in senescent hearts due to impaired utilization of long-chain fatty acid. Aim 3: To test the hypothesis that the increase in glucose uptake during low-flow ischemia is limited in the senescent heart despite increased dependence on glucose utilization during normal perfusion. Aim 4: To test the hypothesis that presence of high glucose and insulin increase glucose utilization and improves the tolerance toischemia in senescent hearts.